Abstract Background Cancer patients receiving chemotherapy have an increased risk of cardiovascular complications. This limits the widespread use of lifesaving therapies, often necessitating alternate lower efficacy regimens, or precluding chemotherapy entirely. Prior studies have suggested that using common cardioprotective agents may attenuate chemotherapy-induced cardiotoxicity. However, small sample sizes and conflicting outcomes have limited the clinical significance of these results. Hypothesis A comprehensive network meta-analysis using updated and high-quality data can provide more conclusive information to assess which drug or drug class has the most significant effect in the management of chemotherapy-induced cardiotoxicity. Methods We performed a literature search for randomized controlled trials (RCTs) investigating the effects of cardioprotective agents in patients with chemotherapy-induced cardiotoxicity. We used established analytical tools (netmeta package in RStudio) and data extraction formats to analyze the outcome data. To obviate systematic bias in the selection and interpretation of RCTs, we employed the validated Cochrane risk-of-bias tools. Agents included were statins, aldosterone receptor antagonists (MRAs), ACEIs, ARBs, and beta-blockers. Outcomes examined were improvement in clinical and laboratory parameters of cardiac function including a decreased reduction in left ventricular ejection fraction (LVEF), clinical HF, troponin-I, and B-natriuretic peptide levels. Results Our study included 33 RCTs including a total of 3,285 patients. Compared to control groups, spironolactone therapy was associated with the greatest LVEF improvement (Mean difference (MD) = 12.80, [7.90; 17.70]), followed by enalapril (MD = 7.62, [5.31; 9.94]), nebivolol (MD = 7.30, [2.39; 12.21]), and statins (MD = 6.72, [3.58; 9.85]). Spironolactone was also associated with a significant reduction in troponin elevation (MD = − 0.01, [− 0.02; − 0.01]). Enalapril demonstrated the greatest BNP reduction (MD = − 49.00, [− 68.89; − 29.11]), which was followed by spironolactone (MD = − 16.00, [− 23.9; − 8.10]). Additionally, patients on enalapril had the lowest risk of developing clinical HF compared to the control population (RR = 0.05, [0.00; 0.75]). Conclusion Our analysis reaffirmed that statins, MRAs, ACEIs, and beta-blockers can significantly attenuate chemotherapy-induced cardiotoxicity, while ARBs showed no significant effects. Spironolactone showed the most robust improvement of LVEF, which best supports its use among this population. Our analysis warrants future clinical studies examining the cardioprotective effects of cardiac remodeling therapy in cancer patients treated with chemotherapeutic agents.